Ghrelin Selectively Inhibits CaV3.3 Subtype of Low-Voltage-Gated Calcium Channels

Abstract

The mechanisms by which ghrelin controls electrical activity in the hypothalamus are not fully understood. One unexploredtarget of ghrelin is CaV3, responsible for transient calcium currents (T-currents) that control neuronal firing.We investigated theeffect of ghrelin on CaV3 subtypes and how this modulation impacts on neuronal activity.We performed whole-cell patch-clamprecordings in primary mouse hypothalamic cultures to explore the effect of ghrelin on T-currents. We also recorded calciumcurrents from transiently transfected tsA201 cells to study the sensitivity of each CaV3 subtype to GHSR activation. Finally, weran a computational model combining the well-known reduction of potassium current by ghrelin with the CaV3 biophysicalparameter modifications induced by ghrelin to predict the impact on neuronal electrical behavior.We found that ghrelin inhibitsnative NiCl2 sensitive current currents in hypothalamic neurons.We determined that CaV3.3 is the only CaV3 subtype sensitive toghrelin. The modulation of CaV3.3 by ghrelin comprises a reduction in maximum conductance, a shift to hyperpolarized voltagesof the I-V and steady-state inactivation curves, and an acceleration of activation and inactivation kinetics. Our model-basedprediction indicates that the inhibition of CaV3.3 would attenuate the stimulation of firing originating from the inhibition ofpotassium currents by ghrelin. In summary, we discovered a new target of ghrelin in neurons: the CaV3.3. This mechanism wouldimply a negative feed-forward regulation of the neuronal activation exerted by ghrelin. Our work expands the knowledge of thewide range of actions of GHSR, a receptor potentially targeted by therapeutics for several diseases.